randomized evidence on monitoring strategies the optimon study€¦ · to compare two monitoring...

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 1 / 26

Valérie JournotINSERM U897 & CIC-EC 7, Bordeaux, France

Randomized evidence on monitoring strategiesthe OPTIMON study

Investigator Pr Geneviève ChêneSponsor Bordeaux University HospitalFunding French Clinical Research Hospital ProgramSupport French university hospitals

INSERMFrench disease-oriented institutions & networksECRIN

https://ssl2.isped.u-bordeaux2.fr/optimon/

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 2 / 26

Back to 2005

European regulationdirective 2001 Clinical Trials

GCP for drug approval trialsin France: any interventional study

GCP widespread interpretation (“gold-standard”)SDV 100% data, 100% patients, 100% sites, on-site monitoring

Protest of (French) academic institutions100% onsite monitoring = 40 to 60% costsefficiency still unprovedhow to optimise cost-efficiency ratio?

cost reduction of on-site monitoring intensity efficiency maintain of fulfilment of regulatory & scientific requirements

the Optimon trial

GCP § 5.18.3 Extent and Nature of Monitoring …The sponsor should determine the appropriate extent and nature of monitoring… In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring… can assure appropriate conduct of the trial in accordance with GCP...

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 3 / 26

Optimon issues

objectiveto compare two monitoring strategies

100% onsite vs. risk-adapted

hypothesisa risk-adapted monitoring strategy can

be defined a priori for each study yield results similar to the 100% onsite strategy for the main quality criteria of studyimprove other aspects, such as costs or delays

a typical non inferiority situation

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 4 / 26

Optimon design

non inferiority trial

ScreeningCTUstudysite

Risk assessmentMonitoring plan

Optimon main eligibility criteriapatient anystudy any clinical field, any design, non risk D level

20 to 100 patients expectedsites 5 patients expectedCTU academic label

experience, GCP compliant

Actions by Optimon team or by study team

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 5 / 26

Optimon design

non inferiority trial

®ScreeningCTUstudysite

risk-adapted

100% onsite

Risk assessmentMonitoring plan

Stratification = risk levelCluster = site

Actions by Optimon team or by study team

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 6 / 26

Optimon design

non inferiority trial

®ScreeningCTUstudysite

risk-adapted

100% onsite

Risk assessmentMonitoring plan

Stratification = risk levelCluster = site

Patients’ inclusion and follow-up

Actions by Optimon team or by study team

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 7 / 26

Optimon design

non inferiority trial

®ScreeningCTUstudysite

risk-adapted

100% onsite

Risk assessmentMonitoring plan

Patients’ inclusion and follow-up

Final cleaningTransfert to Optimon

Actions by Optimon team or by study team

Stratification = risk levelCluster = site

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 8 / 26

Optimon design

non inferiority trial

®ScreeningCTUstudysite

risk-adapted

100% onsite

Risk assessmentMonitoring plan

Patients’ inclusion and follow-up

Final cleaningTransfert to Optimon

Optimon data

collection

Stratification = risk levelCluster = site

Optimon outcomesprimary

% patient file without error onconsent form signature & SAEs reportmain eligibility criteria & primary outcome

secondaryerrors, delays, costs

Actions by Optimon team or by study team

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 9 / 26

Optimon design

non inferiority trial

®ScreeningCTUstudysite

risk-adapted

100% onsite

Risk assessmentMonitoring plan

Patients’ inclusion and follow-up

Final cleaningTransfert to Optimon

Statistical analysisby patient

Stratification = risk levelCluster = site

Actions by Optimon team or by study team

Optimon data

collection

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 10 / 26

Optimon design

non inferiority trial

®ScreeningCTUstudysite

risk-adapted

100% onsite

Risk assessmentMonitoring plan

Patients’ inclusion and follow-up

Final cleaningTransfert to Optimon

Statistical analysisby patient

Stratification = risk levelCluster = site

Actions by Optimon team or by study team

Optimon data

collection

Optimon sample size = 5% / 100%onsite = 95% / intrasite = 0,60 1,800 patientsrevised to 900 = 11%

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 11 / 26

Optimon recruitmentCTU 11Risk level 8 A

4 B10 C

Design 16 trial3 cohort3 cross-sectional

Clinical field 6 cancer3 liver & gastr.enter.3 neurology2 nutrition2 rheumatology1 hematology1 infectiology1 intensive care 1 pneumology1 tabacco1 urology

Population 14 adults4 children2 women2 elderlies

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 12 / 26

1. to assess study characteristicswithout any glance at the resulting risk level

Pre Optimon risk assessment scaleContemp Clin Trials 2011;32(1):16-24

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 13 / 26

1. to assess study characteristicswithout any glance at the resulting risk level

Pre Optimon risk assessment scale

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 14 / 26

1. to assess study characteristicswithout any glance at the resulting risk level

Pre Optimon risk assessment scale

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 15 / 26

2. to deduce the risk level

Pre Optimon risk assessment scale

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 16 / 26

2. to deduce the risk level

Pre Optimon risk assessment scale

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 17 / 26

2. to deduce the risk level

Pre Optimon risk assessment scale

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 18 / 26

100% onsite monitoring risk-adapted monitoringrisk level

Arisk level

Brisk level

C

set-up

initial contact systematically and tracedsite adequation systematically, remotely if site known and experimented

otherwise on site (may be coupled with set-up)initiation systematically, before inclusion of 1st patient, by phone if site known and experimented,

otherwise on site

data monitoring

on-site monitoringdata conformity

respect of procedures

on site, 100% patients,100% data, 100% sites

(freq. to be defined at study start)

10% patients100% key points

then if major problem

1 visit / site100% key points

then is major problemcomprehension of

circuits systematically, on site, at 1st

monitoring visit (from 1st inclusion)systematically, by phone

after reception of forms of 1st patient at CTU/CRCconsents systematically, on site

at next visitmasked copy at inclusion

on site at next visit or at closuresearch for SAEs systematically, on site systematically, on site or remotely

corrections at each visit, 100% dataqueries created remotely or on site

at each visit for key pointsqueries created remotely

forms verification systematically, before entry of forms not checked on site

centralized monitoring systematically, 100% patients, 100% data, 100% sites + respect of procedures

close-outsystematically, on site

100% patients, 100% sitessystematically, par mail

100% patients, 100% sitessystematically, on site

100% patients, 100% sites

Pre Optimon risk-adapted monitoring plan

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 19 / 26

on-site monitoring

key points key data, respect of procedureskey data patient's existence, consent form signature, primary outcome,

main eligibility criteria, main exams and visits, main secondary outcomes

Pre Optimon risk-adapted monitoring plan

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 20 / 26

on-site monitoring

key points key data, respect of procedureskey data patient's existence, consent form signature, primary outcome,

main eligibility criteria, main exams and visits, main secondary outcomes

centralized monitoring

Pre Optimon risk-adapted monitoring plan

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 21 / 26

Rationalehigh inter-assessor variability observed in Pre Optimonneed for risk assessment independent from sponsor validation committee

2 clinicians, 2 methodologists, 2 sponsor representativesindependent assessmentconsensus search if needed

Summary of results24 studies assessedinitial consensus reached for 2/3 studiessponsors tend to a higher risk level

collective risk assessmentby trained assessors

Risk assessment in Optimon

methodologists clinicians sponsors

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 22 / 26

original

Remote checking of consent formClin Trials 2013.10(3):445-55 & 446-8

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TO BE CHECKED

Investigator-signature-name-date of signature-contact info.

Participant-anonymization-name-date of signature-signature

Trial-identification

Consent form-version

original

Remote checking of consent formClin Trials 2013.10(3):445-55 & 446-8

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 24 / 26

TO BE CHECKED

Investigator-signature-name-date of signature-contact info.

Participant-anonymization-name-date of signature-signature

Trial-identification

Consent form-version

original masked copy

something visible, not legible

Remote checking of consent formClin Trials 2013.10(3):445-55 & 446-8

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 25 / 26

Limitsguesstimated sample size and powerrisk for participant only / one-for-all strategy

outdated

Strengthsrandomized clinical trial

high level of evidenceonly 2 such trials: Optimon and Adamon

risk for participant only= minimal level of monitoring

one-for-all strategy proof of concept

movement for development of the approachECRIN, OECD, FDA, EMA, EC (drug) trialsOptimon any study design or phase

Optimon in the regulation changing context

OPTIMON – V. Journot Society for Clinical Trials, Boston, 20 May 2013 26 / 26

Valérie JournotINSERM U897 & CIC-EC 7, Bordeaux, France

Randomized evidence on monitoring strategiesthe OPTIMON study

Investigator Pr Geneviève ChêneSponsor Bordeaux University HospitalFunding French Clinical Research Hospital ProgramSupport French university hospitals

INSERMFrench disease-oriented institutions & networksECRIN

https://ssl2.isped.u-bordeaux2.fr/optimon/